CZ203193A3 - Pharmaceutical preparation containing 1, 5, 6, 7-tetrahydro-4h-inolazol-4-one, novel 1,5,6, 7tetrahydro-4h-inolazol-4-ones and process for preparing thereof - Google Patents

Abstract

The pharmaceutical compositions contain 1,5,6,7-tetrahydro-4H-indazol-4-ones of the formula <IMAGE> where some of these substances are themselves novel. The pharmaceutical compositions are used as analgesics, antipyretics and antiinflammatory agents.

Description

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Technical field

The present invention relates to pharmaceutical compositions »containing 1,5,6,7-tetrahydro-4H-indazol-4-ones _with novel _l> 5, J5, _J7>; .tetrahydror4H-indazol-4-one - Processes for the preparation of these compounds and the use of these compounds in pharmaceutical compositions with analgesic, antipyretic and anti-inflammatory activity.

BACKGROUND OF THE INVENTION 1,5,6,7-Tetrahydro-4H-indazol-4-ones have been described as chemical substances in, for example, J. Het. Chem. 19, 1355 (1982); J. Org. Chem., 52, 4384, 1987, J. Cham. Research, 1401, 1936, J. Chem. Soc., 803 (1953).

The various pharmacological properties of 1,5,6,7-tetrahydro-4H-indazol-4-ones not falling under Formula I below have been reported, for example, in the following publications:

a) Analgatic and anti-inflammatory activity has been reported for some compounds in II Farmaco, Ed.

Sci., 42, 259 (1937); II Farmaco, Ed. Sci., 43, 763, 1933 and U.S. Pat. No. 3,657,438.

b) broncholytic and antibiotic compounds have been described in Heterocyclas 32, 41, 1991, U.S. Patent Nos. 4,734,430 and 4,734,429;

c) compounds having antiviral activity have been described in US Patent No. 3,691,180.

The essence of the invention

It has now been found that zol-4-ones of the general formula: 1,5,6,7-tetrahydro-4H-indole

where _ _::: ____............._______

R and R, the same or different, represent a hydrogen atom, a straight or branched chain alkyl radical o.

to 6 carbon atoms optionally substituted

a phenyl, fluorophenyl, chlorophenyl or bromophanyl group or a phenyl radical optionally substituted by a halogen atom; and

X represents a single chemical bond or a methylene group optionally substituted by one or two alkyl groups having 1 to 3 carbon atoms, i.e., a carbon-to-ethylene-a-group.

and their optically active antipodes having an optically active carbon atom have valuable pharmacological properties, particularly analgesic, antipyretic and / or anti-inflammatory activity;

New are those compounds of formula (I) in which 1 2

R is hydrogen and R is C 2 -C 6 alkyl or those in which R 1 is phenyl

the radical and R ** is a straight or branched alkyl group having 2 to 6 carbon atoms, as well as those compounds,

Wherein R is a halophenyl moiety and R is a straight or branched chain alkyl group having 1 to 6 carbon atoms.

SUMMARY OF THE INVENTION. The present invention also relates to novel pharmaceutical compositions containing, as an active ingredient, a compound of formula (I) for the treatment of pain, fever and inflammation and symptoms of a cold, the present invention also relates to novel 1,5,6. 7-Tetrahydro-4H-indazol-4-one derivatives of formula (I) and a process for the preparation of these compounds.

Particularly effective are the compounds of formula I in which:

R ^ represents a hydrogen atom or a methyl group,

R is methyl, ethyl, propyl, isopropyl, benzyl or phenyl; and

X represents a methylene group optionally substituted by two methyl groups.

Most preferred is a compound of formula I, v

R12 is hydrogen, R is methyl and X is methylene. This group has been described as a starting material for the production of analgesic and anti-inflammatory compounds according to II Farmaco Ed. Sci., 42,259,1987 and Farmaco Ec. Sci., 47, 567, 1992, however, these publications do not disclose any data concerning the possible pharmacological properties of this starting material. It is therefore very surprising that this compound has very good analgesic, antipyretic and anti-inflammatory effects, which was not to be expected.

According to U.S. Pat. No. 3,657,433, a compound of formula I in which R is methyl, R is benzyl, and X is methylene is a starting material for the preparation of compounds with orotizinflammatory activity. However, nothing is stated about the pharmacological properties of this starting material. It has now been unexpectedly found that this substance also has the above-mentioned valuable properties.

The preparation of compounds of formula (I) in which R * is * 2. .atom. v.cdíku.,. R is methyl or phenyl and X is methylene or dimethylmethylene has been described in J. Hat. Chem. 19, 1355, 1932.

Preparation of compounds of formula I wherein R is atom. hydrogen, .. R. means benzyl. and X represents a methylene group is known from Heterocycles

32, 41 (1991)

2 R represents a methyl group, R represents a phenyl group and X represents a methylene group was. described .v. J. Chem. Soc., 803, 1953.

The above-mentioned new 1,5,6,7-tetrahydro-4E-indazol-4-one derivatives can be prepared by the method of the invention according to the following procedures:

(a) a compound of formula (X) wherein R ^{* 1} is as defined above except for a hydrogen atom may be obtained by reacting a compound of formula (X) TT

where

X is as defined above and

R ^ is as defined above except for the hydrogen atom, with the hydrazine III

H ₂ N-NH-R ^{* 2} (III) 2 wherein R is as defined above.

The reaction is preferably carried out in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, dioxane, methylene chloride or benzene at a temperature of from 0 ° C to the reflux temperature of the reaction mixture. The resulting products can be isolated in a known manner by removing the solvent.

b) Compounds of formula I wherein R R is hydrogen can be prepared by reacting a compound of formula IV

where

X. has the above meaning and ....... .

R @ 1 is preferably alkyl. with a hydrazine of formula III.

The general formula (III) with compound ( ^{4) of} formula (IV) is carried out in methanol, ethanol, isopropanol, tetrahydrofuran, dioxane and methylene chloride by dissolving the compounds individually in these solvents and then mixing the solutions at 0 ° C.

Then, the resulting reaction mixture is stirred for several hours at 0 ° C to the reflux temperature of the reaction mixture, whereupon the solvent is removed, for example by distillation.

The starting materials of the formula II can be obtained according to the method of J. Chem. Soc., 803, 1953 and Synthesis 925, 1973. The preparation of the starting materials of the general formula IV has been described in J. Het. Chem. 19, 1355 (1932).

As already mentioned, the compounds of the formula I have valuable pharmacological properties, in particular antipyretic, analgesic and anti-inflammatory effects.

In particular, compound A, 1-methyl-1,5,6,7-tetrahydro-4H-indazol-4-one has been tested:

1. Tests for the efficacy of this compound against inflammatory pain were performed in rats according to the method of Ra.ndall and Selitto, Arch. Int. Pharmacodyn. 111, 409 (1957). The test compound was administered to male rats weighing 100-130 g in an amount of 1.0 ml per 100 g animal weight as a 1 µM meth. 90. mi-nut, -ρο- underneath it will give you a hek swallow probe. Depending on the pain read off after administration of single doses at 45, 90 or 130 minutes after administration, the dose was calculated after a linear regression analysis as a dose that reduces the pain to percent. The values obtained are shown in the following table:

ii J compound EDpo 45 min for 90 min

A 3.1 2.1

2. Tests for the efficacy of the compound against heat pain in mice were performed according to the method of Chen and Beckman,

Science 113, 631, 1951. Male mice with an average weight of 20 g received the test compound in 1% methylcellulose at a dose of 0.1 ml per 10 g animal by gavage. From the prolongation of the reaction time after the different doses administered, the dose was calculated by linear regression analysis as a dose which resulted in a doubling of the reaction time. The values obtained are shown in the following table:

-8 -.

compound

Not more than mg / kg

159

Assays for activity against mechanically induced shaving were performed using a mouse tail clamp according to Haffner, Dtsch. copper. Wschr., 54, 731, 1929. Male mice weighing 19 to-AZ- -21 g-being of koumaná substance is administered in 1% methylcellulose at a dose of 0.1 ml per g of animal weight Io pblýkáčí ^- sondou'.Vodstupu ''' The number of mice no longer responding to the clamp placement was monitored for 30 minutes.

From the percentage of animals that did not respond to the painful stimulus after different doses, the dose was calculated using probit analysis

The values obtained are shown in the following table:

compound ^ED 50

A 45.2

4. Body temperature activity tests were performed in normal temperature rats weighing 120-140 g. The test substance was administered in 1% methylcellulose at a dose of 1.0 ml per 100 g animal swallow. From the decrease in rectal temperature that occurred after. administration of various doses of the test substance was calculated by a linear regression analysis as the dose at which the body temperature decreased by 1.5 ° C.

The values obtained are shown in the following table:

Compound ^ED -1.5 ° C

7.1

5. The acute toxicity determination was performed in mice or rats of both sexes with a mean weight of 20 g. The test substance was administered in 1¾ methylcellulose at a dose of 0.2 ml / 10 g of animal weight by gavage. The calculation of the LD-θ value was, if possible, performed according to Lichtfield and Wilcoxon, J. Pharmacol. exp. Therap., 95, 99, 1949 based on the percentage of animals that died after administration of various doses over 14 days.

The values obtained are shown in the following table:

compound rat rat

A 1570 1090

Owing to their pharmacological properties, the compounds of the formula I can be classified as analgesic and antipyretic substances of the aminophenazone type. For this reason, they are useful in headaches, teeth, nerves, migraine and postoperative and trauma pains, but also in the treatment of fever and inflammatory conditions, for example in the case of cold symptoms.

For this purpose, the compounds of the formula I can optionally be treated in combination with other active ingredients, with one or more inert carriers and / or diluents, for example water, corn starch, potato starch, milk or cane sugar, microcrystalline cellulose, magnesium stearate , polyvinylpyrrolidone, solid fats, carboxymethylcellulose or a suitable mixture thereof into conventional galenic dosage forms, such as tablets, dragees, capsules, powders, suppositories, suspensions or solutions. ' ------------ between -25- to -1200- mg, preferably at a rate of about 50 to about. .6.00. and ... in particular

300 mg.

The following examples illustrate the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

1-methyl-1,5,6,7-tetrahydro-4H-indazol-4-one

A solution of 46.1 g (1.0 mol) of methylhydrazine in 400 ml of methanol is slowly added dropwise to a solution of '157.2' (1.0 mol) of 2- (dimethylaminomethyl-en) cyclohexane-1,3-dione at room temperature. in 2000 ml of methanol. The reaction mixture was then stirred at reflux for 1.5 hours. The mixture was evaporated to dryness in vacuo and the crude product was purified by silica gel chromatography (Baker, 30-60 microns) eluting with 9: 1 ethyl acetate: cyclohexane.

Recrystallization from diisopropyl ether afforded the title compound as a colorless crystals in a yield of 39.3% of theory, mp 96-97 ° C.

Example 2

1-ethyl-1,5,5,7-tetrahydro-4H-indazol-4-one

The procedure of Example 1 was followed except that ethylhydrazine and 2 (dimethylaminomethyl-ene) -cyclohexane-1 'were used as starting materials; -3 - aperture. · *

Melting point: 60-61 ° C

Yield: 83% of theory.

Example 3

1-Propyl-1,5,6,7-tetrahydro-4H-indazol-4-one

The procedure of Example 1 was followed except that propylhydrazine a was used as the starting material

2- (dimethylaminomethylene) cyclohexane-1,3-dione.

Melting point: 47 to 48 ° C

Yield: 70% of theory.

Example 4 1- (1-methylethyl) -1,5,6, T-tetrahydro-1H-indazol-1-one

The procedure of Example 1 was followed except that isopropylhydrazine and 2- (dimethylaminomethylene) cyclohexane-1,3-dione were used as starting materials.

Melting point: 34-35 ° C

Yield: 53% of theory.

and

Example 5

1-Benzyl-1,5,8,8-tetrahydro-4H-indazol-4-one

The procedure of Example 13 was followed except that benzylhydrazine a was used as the starting material

2- (dimethylaminomethylene) cyclohaxane-1,3-dione.

Melting point: 60 ° C

Yield: 72% of theory. '/

Example 6

1-phenyl-1,5,6,7-tetrahydro-4H-indazol-4-one

The procedure of Example 1 was followed except that phenylhydrazine a was used as the starting material

2- (dimethylaminomethylene) cyclohexane-1,3-dione.

Melting point: 140 ° C

Yield: 49% ^- 'quantity .........

Example 7

1,6, o-trimethyl-1,5,6,7-tetrahydro-4H-indazol-4-one

The procedure of Example 1 was followed except that methylhydrazine was used as the starting material. and 2- (dimethylaminomethylene) -5,5-dimethylcyclohexane-1,3-dione Melting point: 74 to 75 ° C

Yield: 32% of theory.

Example 8 1-ethyl-3-methyl-1,5,6,7-tetrahycro-4H-indazol-4-one

Following the procedure of Example 1, except that used as starting material 2-acetylcyklohe: CAA-1,3-dione and pthyl hynr ^ -Z n. _{W. n} . _ 'm

Melting point: 66-67 ° C

Yield: 43% of theory.

Pharmaceutical examples

Example I

Tablets containing 125 mg 1-methyl-1,5,6,7-tetrahydro-4Hindazol-4-one ingredient mg active ingredient 125.0 microcrystalline cellulose 63.5 directly tabletable milk sugar 110.0 magnesium stearate -1.5 '

300.0 mg

Production:

The excipients are intimately mixed with the active ingredient and compressed into tablets. Round flat tablets are obtained, on one side of which there is a score line.

Tablet weight: approximately 300 mg

Tablet diameter: 10 mm.

- 14 Example II

Dragees containing 125 mg of 1-methyl-1,5,5,7-tetrahydro-4H-indazol-4-one

Ingredient mg Active Ingredient 125.9 Microcrystalline cellulose 63.5 Direct-labable milk sugar 110.0 Magnesium staarate. ........ 1,5

300.0 mg

Production:

The excipients are intimately mixed with the active ingredient and the mixture is compressed into dragee cores. The cores obtained are coated in a conventional manner using a slurry of sugar and then pure sugar syrup in a quantity of 390 .mu.g per dragee in the coating drum.

Dragee weight: approximately 300 mg Dragee diameter: 10 mm

Design: o.klouk biconvex dragees.

Example III

Granulate containing 1-methyl-1,5,6,7-tetrahydro-4H-indazol-4-one in%

Component

(01) active ingredient 12.5 (02) sorbit 86.0 (03) silica 1.3 (04) magnesium staaran 0.2

100.0

Production:

Components 01, 02 and 03 are mixed and wet granulated after addition of ethanol. After drying and passing through a 1.0 mm sieve, the granulate is blended with a component of 0.4 and filled into sachets, each sachet containing 1 g of granulate containing

125 mg of the active substance. . . ~ 11111,, 1110 »»

.... ......

Example IV

Fine granulate containing 1-methyl-1,5,6,7-tetrahydro-4H-indazol-4-one component in%

(Cl) active substance 12.5 (02) polyvinylpyrrolidone 2.3 (03) lactose 33.0 (04) silica 1,2 (05) magnesium stearate 0.5

100.0

Production:

A component 03 having a particle size of 0.2 to 0.45 mm is placed as a template in the rotating drag drum.

The component 02 is dissolved in isopropanol and then the components 01 and 04 are suspended therein. The suspension is sprayed with the aid of dry air carefully to the lactose crystals in the coating drum. After drying, component 05 is added and the granulate is filled into sachets in an amount corresponding to 125 mg of the active ingredient.

and

Example V

1-6

Solution for injection containing 125 mg of 1-methyl-1,5,6,7-tetrahydro-4H-indazol-4-one ingredient amount active substance 125.0 mg water for injections up to 2.0 ml

The active substance is dissolved in water for injection at room temperature. The solution is sterilized by filtration, filled into clean ampoules and then autoclaved at 121 ° C for 20 minutes. .....

J.

Example VI suppositories containing ‘2‘QQ mg'1-melamine 'I-I75', '677-phenoxy-4'K'-' indazol-4-one ingredient mg active ingredient 7 200.0 solid fat, for example Vititspsol H 19 or Witepsol W 45 1 500.0

Production:

The solid fat melts and the active ingredient is dispersed homogeneously at 33 ° C. The dispersion is cooled to 35 ° C and filled into slightly pre-cooled suppository molds.

Example VII

Syrup 3 contains 125 mg of 1-methyl-1 -4H-indazol-4-one component , 5,5,7-te trahydro- delay active substance carboxymethylcellulose 0,10 g p-hydroxy- methyl ester benzoové 0.05 g propyl p-hydroxy- benzoové 0,03 g sucrose 10,00 g glycerol 5,00 g sorbitan spread 70% 20,00 g aromatic substances 0,30 g distilled water to 100,00 ml Production: Distilled water is heated to 70 ° C. With stirring methyl ester and propyl ester are added r of p-hydroxy-

benzoic / glycerol and carboxymethylcellulose, all components are dissolved, the mixture is cooled to room temperature and the active ingredient is added and dissolved with stirring. After addition and dissolution of sucrose, sorbitol solution and flavorings, air is removed under reduced pressure and stirring.

Represented by:

Claims (10)

PATENT CLAIMS Pharmaceutical composition with analgesic, antipyretic and anti-inflammatory effects, characterized in that it comprises a compound of the general formula I wherein: 1 2 R and R are the same or different hydrogen, straight or branched chain alkyl of 1 to 6 carbon atoms, optionally substituted by phenyl, fluorophenyl, chlorophenyl or bromo-phenyl, or phenyl optionally substituted by halogen, and X represents a single chemical bond or a methylene group optionally substituted by one or two alkyl groups of 1 to 3 carbon atoms or an ethylene group and one or more inert carriers and / or diluents. A pharmaceutical composition according to claim 1, characterized in that it comprises a compound of formula (I), wherein R 1 is a compound of formula I. represents a hydrogen atom or a methyl group, R is methyl, ethyl, propyl, isopropyl, benzyl or phenyl; and X represents a methylene group optionally substituted by two methyl groups. A pharmaceutical composition according to claim 1- and * 2. ^ "_ ·· - · π ·-ιΊ ... ^'1 - * · v" y * z on characterized in that it comprises slou1 Cenan cbecneho formula I wherein R represents vodixu, R is methyl and X is methylene. 4. A pharmaceutical composition according to any one of claims 1-3, characterized m that it is intended for the treatment of pain, pyrexia and inflammation, and also ^one of the symptoms of catarrhal diseases. Use of the compounds according to at least one of claims 1 to 3 for the manufacture of a pharmaceutical composition for the treatment of pain conditions, feverish conditions and inflammations, as well as symptoms of cold diseases. A process for the preparation of a pharmaceutical composition according to claims 1 to 3, characterized in that the compound according to at least one of claims 1 to 3 is treated in a non-chemical manner together with one or more inert carriers and / or diluents. 7. The 1,5,5,7-tetrahydro-4H-indazol-4-yne derivatives of the general formula I where it is hydrogen, R ² represents a straight- use or branched chain of 2 to S carbon atoms and X represents m -thylanic groups, optionally with one or two methyl groups. 3. 1,5,5,7-Tetrahydro-4H-indazol-4-one derivatives of the general formula I R ¹ represents a phenyl radical optionally substituted by a halogen atom, R represents a straight or branched chain alkyl group having 1 to 6 carbon atoms, optionally substituted by a phenyl or halophenyl radical, and &lt; X represents a methylene group optionally substituted by one or two methyl groups. 9. 1,5,5,7-Tetrahydro-4H-incazol-4-one derivatives of the general formula I wherein 12, R and R are as defined in claim 1 and I X represents a single chemical bond or an ethylene group. A process for the preparation of 1,5,6,7-tetrahydro-4H-indazol-4-one derivatives of the general formula I according to claims 7, 3 and 9, characterized in that (a) reacting a compound of formula II i in the preparation of compounds of formula I in which R 'is as defined above except for hydrogen j; O < ---- 22 -where X is as defined above, and R is as defined above, except for a hydrogen atom, with a hydraziner of formula III H ₂ H - NH - R ² (III) where 1 R. ' mentioned above, or meaning 333333333. ...> ----- - - - ^j ~ V V 7 Í 7 7 b) reacting a compound of formula IV wherein X is as defined above in the preparation of compounds of formula I wherein R is hydrogen; and ... ....... R is an alkyl group, with a hydrazine of formula III. Process according to claim 10, characterized in that the reaction is carried out in an organic solvent at a temperature of 0 ° C to the reflux temperature of the reaction mixture.